This proposal will test the hypothesis that measures of brain atrophy will prove to practical, sensitive, and relevant surrogate markers of the disease process in multiple sclerosis patients. The need for a surrogate marker is based on emerging evidence that the pathologic process in MS irreversibly damages myelin and axons, that this process is active from disease onset, but that clinical symptoms only loosely reflect the severity of the underlying pathology in the relapsing remitting stage of the disease. By the time an MS patient enters the secondary progressive stage, tissue destruction has progressed beyond the point where compensatory mechanisms can sustain neurologic function. A highly reproducible method for quantifying the extent of brain parenchymal loss, termed the brain parenchymal fraction (BPF), will be used to accomplish the first three specific aims. In aim 1, the pattern with which MS patients develop atrophy will be determined using a longitudinal study design involving 145 MS patients and 30 healthy controls. The purpose of aim 2 is to determine clinical correlates of cerebral atrophy and to test the hypothesis that cerebral atrophy in the relapsing phase of MS predicts later conversion to secondary progressive MS. In aim 3, MRI and CSF correlates of cerebral atrophy will be determined. The significance of specific MR lesion. Types will be inferred from their relationship to cerebral atrophy. The significance of these specific MR lesion types will be directly tested using clinical-MRI correlation derived from autopsy material in aim 4. This project will lead to improve methods for monitoring the pathologic process during the course of MS. The long term clinical goals of this project are to develop methods to promote improved disease management for individual MS patients, and to develop improved monitoring techniques for experimental therapies, including neuroprotective factors.